IRBM, Merck Research Laboratories Rome, Via Pontina km 30,600, Pomezia, 00040 Rome, Italy.
Bioorg Med Chem Lett. 2011 Sep 15;21(18):5283-8. doi: 10.1016/j.bmcl.2011.07.030. Epub 2011 Jul 14.
Smoothened (Smo) antagonists are emerging as new therapies for the treatment of neoplasias with aberrantly reactivated hedgehog (Hh) signaling pathway. A novel series of 4-[3-(quinolin-2-yl)-1,2,4-oxadiazol-5-yl]piperazinyl ureas as smoothened antagonists was recently described, herein the series has been further optimized through the incorporation of a basic amine into the urea. This development resulted in identification of some exceptionally potent smoothened antagonists with low serum shifts, however, reductive ring opening on the 1,2,4-oxadiazole in rats limits the applicability of these compounds in in vivo studies.
smoothened（Smo）拮抗剂作为一种新型治疗方法，正在用于治疗 Hedgehog（Hh）信号通路异常激活的肿瘤。最近，人们描述了一系列新型的 4-[3-(喹啉-2-基)-1,2,4-恶二唑-5-基]哌嗪基脲类 smoothened 拮抗剂，在此基础上，本研究进一步通过在脲基中引入碱性胺对其进行优化。这一发展确定了一些非常有效的 smoothened 拮抗剂，其血清转化率低，然而，在大鼠中 1,2,4-恶二唑的还原开环限制了这些化合物在体内研究中的适用性。
